Utility of Seizure Pattern and Related Clinical Features in the Diagnosis of Neurometabolic Disorders.

Objectives The current study aimed at identifying the role of seizure types and related clinical features in differentiation between neurometabolic disorders and other causes of seizure. Materials & Methods The current cross sectional study was conducted at two referral children hospitals in Tehran, Iran, from 2011 to 2018. The study population included 120 patients presenting with seizure due to neurometabolic disorders and 120 cases due to other causes. The types of seizure and related clinical findings were assessed in both groups. Results: There was a significant difference in the frequency of seizure types in the two groups. Tonic and myoclonic seizures as well as infantile spasm were observed more commonly in the patients with neurometabolic disorders, while atonic, partial and generalized tonic-clonic seizures were more common in the control group. In addition, frequency of refractory seizure, age at onset of seizure, and pattern of involvement in brain imaging were helpful for differentiation. Conclusion: The pattern of seizure and related findings varied in patients with metabolic disorders, and was helpful for diagnosis. Thus, these factors can contribute to early diagnosis and treatment.


Introduction
Inborn Error of metabolism (IEM) is a group of disorders in which genetic abnormalities at the cellular level result in the lack or dysfunction of specific enzymes, cofactors, or transporters required for fatty acid, amino acid, or carbohydrate metabolism (1). Some IEM disorders affecting the nervous system are considered as neurometabolic disorders. Brain is susceptible to damage in such situations (2). Seizure is a common manifestation in neurometabolic disorders and may be considered  (1,2,(4)(5)(6). Therefore, some specific features are reported in seizures along with neurometabolic disorders (7).
Early onset seizures and refractory seizures accompanied by developmental disabilities are commonly observed in IEM disorders (8).
Regarding seizure, clinical findings are often nonspecific (9,10), and high index of suspicion is needed to consider neurometabolic disturbances.

Statistical analysis
Continuous data were expressed as mean ± standard deviation and categorical data as frequency and percentage. In order to compare the characteristics and outcomes between the two groups, independent samples t-test, the Mann Whitney and Chi-squared tests were applied and the exact P-values were calculated whenever needed. The significance level was set at 0.05 and SPSS version 21 was used for data analysis.

Results
Of the visited 213 patients with neurometabolic disorders, 55% (n=120) had seizure disorder (case  Table 1. Distribution of the types of seizure was significantly different between the two groups (P <0.001); tonic and myoclonic, infantile spasm, and mixed-type seizures were more common in the case group, while atonic, absence, partial, and GTC seizures were more frequently observed in the control group, data are shown in Table 3 Parental consanguinity was significantly higher in the case group subjects compared with the control group ones (82.5% vs. 22.5%; P <0.001), Table   3. Overall, 95% of patients in the case group and 5% in the control group had abnormal neurologic status (P <0.001). For example, ocular problems were observed in 31.7% of the cases and none of the controls (P <0.001). Dysmorphic feature was noted in 10.8% of the subjects in the case group and none of the control group patients (P <0.001).
Skin and hair problems were observed in a quarter of the patients in the case group and none of the control group subjects (P <0.001). Also, hearing impairment was detected in 9.1% of the case group patients (5.8% with hyperacusis and 3.3% with hearing loss) and none of the control group subjects (P=0.009). white matter involvement was seen in 23 and brain atrophy in 50 cases. In six patients brain atrophy was associated with basal ganglia involvement , and two cases had white matter involvement along with basal ganglia anomaly. Infarct was observed in two patients ,too. (Figure 1).   Previous studies revealed that seizure is a common presentation of neurometabolic disorders to such an extent that 40%-90% of patients with such problems experience seizure (2,11). Several studies indicated that some types of seizure are more common in neurometabolic disorders; e g, infantile spasm and myoclonic seizure (2,12).
In the current study, seizure started earlier in patients with neurometabolic disorders than the subjects in the control group (mean age: 39.86 vs. 73.76 months), which was in accordance with previous studies that reported ≤12 months old